What is the next test to perform to rule out genetic reasons for elevated iron levels with normal total iron-binding capacity (TIBC), iron saturation, and liver function?

Genetic Testing for Elevated Iron Levels

For patients with elevated iron levels and normal total iron-binding capacity, transferrin saturation, and liver function, HFE gene mutation analysis should be performed as the next test to rule out genetic causes of hemochromatosis.

Diagnostic Approach for Suspected Hemochromatosis

Initial Assessment of Iron Status

• Your current laboratory findings show elevated ferritin (1,059) with normal transferrin saturation, total iron binding capacity, and liver function tests 1
• This pattern is unusual for classic HFE-related hemochromatosis, which typically presents with elevated transferrin saturation (>45%) as the earliest and most sensitive marker 1, 2
• However, genetic testing is still indicated as some non-classical forms of hemochromatosis can present with isolated ferritin elevation 1, 3

Recommended Next Step: HFE Gene Mutation Analysis

• Testing for the C282Y and H63D mutations in the HFE gene should be performed as the next diagnostic step 1
• This is the most cost-effective approach to determine if you have the most common genetic cause of hereditary hemochromatosis 1, 2
• The C282Y mutation is present in approximately 90% of patients with hereditary hemochromatosis, with most being homozygous for this mutation 1

Interpretation of HFE Testing Results

• If you are homozygous for C282Y (C282Y/C282Y), this confirms the diagnosis of HFE-related hemochromatosis 1
• If you are compound heterozygous (C282Y/H63D) or H63D homozygous with confirmed iron overload, further investigation for other causes of iron overload is needed 1
• If HFE testing is negative or shows only heterozygosity for C282Y or H63D, proceed to testing for rare hemochromatosis gene variants 3, 4

Testing for Non-HFE Hemochromatosis

When to Consider Testing for Rare Variants

• If HFE gene testing is negative or non-diagnostic (simple heterozygosity) but iron overload persists, testing for mutations in other iron-regulatory genes is indicated 3, 4
• Up to 30% of patients with a hemochromatosis phenotype in Mediterranean regions may have a negative or non-diagnostic HFE test 4

Genes to Test in Non-HFE Hemochromatosis

• Testing should include sequencing of additional genes involved in iron metabolism: 3, 4
  • Hemojuvelin (HJV) - especially in patients under 30 years with cardiac or endocrine manifestations 3
  • Hepcidin (HAMP) 3, 5
  • Transferrin receptor 2 (TFR2) 3, 4
  • Ferroportin (SLC40A1) 3, 4

Advanced Testing Methods

• Next-generation sequencing (NGS) panels targeting all five hemochromatosis genes (HFE, HJV, HAMP, TFR2, SLC40A1) provide a comprehensive "second level" genetic test for patients with unexplained iron overload 4
• This approach is particularly useful for identifying rare or novel mutations in patients with a hemochromatosis phenotype but negative for common HFE mutations 4, 5

Clinical Considerations and Pitfalls

Important Caveats in Interpretation

• Serum ferritin can be elevated due to inflammation, liver disease, or other conditions unrelated to iron overload 2, 6
• Before proceeding with genetic testing, common causes of hyperferritinemia should be excluded, including: 1
  • Chronic alcohol consumption
  • Inflammatory conditions (check C-reactive protein)
  • Cell necrosis (check liver enzymes and creatine kinase)
  • Malignancy
  • Non-alcoholic fatty liver disease and metabolic syndrome

Follow-up After Genetic Testing

• If genetic testing confirms hemochromatosis, family screening of first-degree relatives is recommended 1
• A liver biopsy may be considered in C282Y homozygotes with serum ferritin above 1,000 μg/L, elevated liver enzymes, hepatomegaly, or age over 40 years to assess for cirrhosis 1
• Patients with confirmed hemochromatosis should avoid alcohol and raw seafood (due to risk of Vibrio vulnificus infection in iron-overloaded patients) 1